ICC Con FC Normal 2011

REVIEW
Heart Failure with Preserved Ejection Fraction:

Pathophysiology and Emerging Therapies
Aaron M. From & Barry A. Borlaug
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, MN, USA
Keywords
Diastole; Heart failure; Heart failure with
preserved ejection fraction; Hypertension;
Pathophysiology; Treatment.
Correspondence
Barry A. Borlaug, M.D., Mayo Clinic, 200 First
Street SW, Rochester 55905, MN, USA.
Tel: 507-284-4442;
Fax: 507-255-2550;
E-mail: borlaug.barry@mayo.edu
Approximately half of patients with heart failure (HF) have a preserved ejection fraction (HFpEF). Morbidity and mortality are similar to HF with reduced
EF (HFrEF), yet therapies with unequivocal benefit in HFrEF have not been
shown to be effective in HFpEF. Recent studies have shown that the pathophysiology of HFpEF, initially believed to be due principally to diastolic dysfunction, is more complex. Appreciation of this complexity has shed new light
into how HFpEF patients might respond to traditional HF treatments, while
also suggesting new applications for novel therapies and strategies. In this review, we shall briefly review the pathophysiologic mechanisms in HFpEF, currently available clinical trial data, and finally explore new investigational therapies that are being developed and tested in ongoing and forthcoming trials.
doi: 10.1111/j.1755-5922.2010.00133.x
Introduction
Approximately half of patients with heart failure (HF)
have a preserved ejection fraction (HFpEF) [1]. Morbidity
and mortality are similar to HF with reduced EF (HFrEF)
[1,2], yet therapies with unequivocal benefit in HFrEF
have not been shown to be effective in HFpEF [35]. Recent studies have shown that the pathophysiology of HFpEF, initially believed to be due principally to diastolic
dysfunction [610], is more complex [1124]. Appreciation of this complexity has shed new light into how HFpEF patients might respond to traditional HF treatments,
while also suggesting new applications for novel therapies
and strategies. In this review, we shall briefly review the
pathophysiologic mechanisms in HFpEF, currently available clinical trial data, and finally explore new investigational therapies that are being developed and tested in
ongoing and forthcoming trials.
Pathophysiology of HFpEF
Recent studies have substantially improved our understanding of pathophysiology in HFpEF. Table 1 describes
e6
the central mechanisms described to date, their hemodynamic effects and how they are believed to contribute to
clinical behavior and symptoms in HFpEF.
Diastolic Dysfunction
Diastolic dysfunction is characterized by impairments in
ventricular relaxation and chamber stiffness during filling
[610]. Abnormalities in each have been well described
in patients with HFpEF, though diastolic dysfunction is
often present in asymptomatic patients without HF, particularly with normal aging, hypertension and in the setting of concentric ventricular remodeling [25]. The majority of patients with HFpEF and diastolic dysfunction
have a history of hypertension [10,17,26], and it is speculated that changes in ventricular structure and function in response to the latter create the substrate upon
which HFpEF is formed [10,22]. As patients with hypertensive heart disease acquire additional abnormalities in
ventricular-vascular function (discussed subsequently),
there may be transition from the asymptomatic patient (ACC/AHA Stage B) to symptomatic heart failure
(Stage C) [27]. It is widely [8,9] though not universally
c 2010 Blackwell Publishing Ltd

Cardiovascular Therapeutics 29 (2011) e6e21
Heart Failure with Preserved Ejection Fraction
A.M. From and B.A. Borlaug
Table 1 Pathophysiologic mechanisms of heart failure with preserved ejection fraction

Mechanism
Hemodynamic effects
Clinical sequelae
References
Ventricular diastolic
dysfunction
1. LV relaxation rate and

diastolic stiffness lead to LV
lling pressures
2. Secondary pulmonary
hypertension
3. FrankStarling reserve with
exercise
Dyspnea at rest or exertion

Pulmonary congestion/edema
Fatigue/effort intolerance
Systemic edema and congestion
Kitzman [6], Gandhi [7], Zile [8],

Lam [10], Westermann [9], Phan [24],
Tan [23], Chatto-hadpyay [42]
Ventricular systolic
dysfunction
1. Minimal effects at rest

2. Contractile reserve with
exercise:
a. Stroke volume reserve
b. LV end systolic volume with
exercise may diastolic reserve
Minimal sequelae at rest

Liu [47], Yip [12], Yu [13], Petrie [14],

Borlaug [15, 22, 40], Ennezat [19],
Tan [23], Phan [24],
Ventricular systolic
stiffening
1. Changes in blood pressure

with alterations in preload or
afterload
2. Contractile and stroke volume
reserve with exercise
3. LV work required to eject given
stroke volume
Hypotension and oliguria with

slight overdiuresis or addition of
a new vasodilator
Hypertensive crisis
Myocardial oxygen demand with
ischemia/angina
Chen [51], Kawaguchi [11], Borlaug

[22,39], Lam [10]
Vascular stiffening and

dysfunction
1. LV afterload-stroke volume
reserve
2. LV relaxation due to #1
3. Exercise vasodilation
4. Endothelial Dysfunction
Hypertensive response to exercise

Myocardial oxygen demand with
ischemia/angina
Kawaguchi [11], Hundley [52], Borlaug

[15, 30, 39, 50], Ennezat [19],
Leite-Moreira [31,32],
Neuro-hormonal
activation
1. Extracellular uid volume

2. Cardiac lling volumes and
consequent lling pressures

Fatigue/fffort intolerance
Systemic edema/congestion
Maurer [16, 18], Kitzman [119],

Abramov [68]
Left atrial dysfunction
1. Atrial contractility and atrial

contractile reserve
2. Atrial remodeling

Atrial brillation
Melenovsky [17], Gottdiener [54]

Fung [55]
Pulmonary hypertension
1. Right ventricular afterload

2. RV stroke volume reserve
3. RV remodeling

Systemic edema/congestion
Klapholz [26], Lam [21], Kjaergaard [56]
Autonomic dysfunction
1. Chronotropic incompetence
2. Sympathetic hyperactivation
Exertional dyspnea
Effort intolerance and fatigue
Borlaug [15], Brubaker [41]

Kasama [44], Phan [45]
Skeletal muscle
dysfunction
1. Impaired vasodilation
2. Sympathetic hyper-activation
and ergoreex stimulation
Muscle wasting
Exertional dyspnea
Clark [65]
Witte [64]
Anemia
1. Cardiac output to maintain

oxygen delivery
2. Viscosity
Exertional dyspnea
Angina/ischemia
Felker [69], Latado [71]

Abramov [68]
Groenveld [70]
Described in HFrEF and presumed to contribute to HFpEF but not described.

e7
[28] believed that diastolic dysfunction lies at the center

of the process, though it is now clear that multiple nondiastolic abnormalities also contribute. When younger patients present with HFpEF, particularly in the absence of
a history of hypertension, hypertrophic, restrictive, or infiltrative cardiomyopathy should be suspected [16]. These
patients tend to display the most dramatic extremes of diastolic dysfunction and can be very difficult to treat.
Diastolic dysfunction may be due to processes operating at the level of the sarcomere, myocyte, extracellular matrix, and chamber, each of which represents a
potential therapeutic targetthese processes have been
reviewed in detail elsewhere [25]. Despite a wide array
of potential targets, there are no currently approved oral
therapies that directly treat diastolic dysfunction. There
is substantial evidence that elevated afterload impairs diastolic function, suggesting that vasodilators may indirectly treat diastolic abnormalities [2934]. Inotropes enhance diastolic relaxation directly by affecting calcium
handling and sarcomeric thickthin filament interaction,
and indirectly by decreasing ventricular end-systolic volume, which increases elastic recoil during early diastole
[25,35], but currently available inotropes increase mortality in HFrEF and have no role in the treatment of HFpEF [27]. Because diastolic dysfunction is felt to result
largely from maladaptive ventricular remodeling, therapies which treat this remodeling may improve diastolic dysfunction or prevent/delay its development [25].
Investigational therapies directly targeting diastolic dysfunction are discussed further.
Systolic Dysfunction
Ejection fraction is normal or near-normal in HFpEF,
both at rest and during acute pulmonary edema [7], but
EF in itself is not a robust measure of contractility. At the
same contractility level, EF tends to increase slightly with
increases in preload, while it decreases markedly with
acute elevations in afterload [36]. Numerous studies have
shown that measures of regional systolic function, most
frequently measured by Tissue-Doppler or strain echocardiography, are depressed in HFpEF [1214,17,37,38]. Abnormal myocardial shortening or thickening has been
shown principally in the longitudinal axis, but recently
abnormalities in radial deformation, twist and untwist
have been observed [20,23]. Because diastolic filling is
enhanced by ventricular untwisting or recoil during early
diastole, systolic dysfunction may promote diastolic dysfunction via this cross talk [35,39]. Similar to EF, these
regional measures of systolic shortening or thickening,
vary inversely with afterload [30], which is often elevated in HFpEF, suggesting that part of this abnormality
may be related to chronic increases in ventricular load.
e8
Using load-independent measures, Baicu et al. found no

difference in global chamber systolic function comparing HFpEF patients to healthy controls [38]. More recently, a larger-sized, population-based study found that
despite preservation of EF, chamber-level and myocardial
contractility are subtly but significantly depressed in HFpEF, and intriguingly, more severe contractile dysfunction in HFpEF was shown to predict increased mortality
[22]. Whether or how mild systolic dysfunction in HFpEF
should be treated remains unclear, but as discussed subsequently, even mild deficits in resting systolic function
may become extremely limiting under stress conditions,
such as with exercise [15,19,23,24,40,41].
Cardiovascular Reserve Function in HFpEF

The majority of earlier mechanistic studies focused on
measuring indices of cardiovascular function under resting conditions. However, most patients with HFpEF complain of symptoms predominantly during exercise [26].
A number of recent studies have highlighted the importance of abnormalities in ventricular-vascular reserve in
HFpEF, defined by the change in a given measure of
cardiovascular function with stress [6,19,23,24,4042].
Kitzman et al. showed that diastolic reserve function is
blunted in HFpEFpatients displayed less increase in
ventricular preload (end-diastolic volume) with exercise
than controls, despite marked elevations in ventricular filling pressures [6]. However, this study was small
(n = 7) and nearly half of the subjects had hypertrophic
or infiltrative cardiomyopathydiseases known to produce the most dramatic extremes of diastolic dysfunction.
These results may be less relevant to patients with diastolic dysfunction related to hypertensive heart disease.
Recent studies have confirmed greater increases in diastolic pressures with exercise in HFpEF, though intriguingly, acute exercise changes in diastolic relaxation and
stiffness were no different than those observed in controls [9]. A recent tissue-Doppler study noted impaired
enhancement in early relaxation (E velocity) with dobutamine stimulation in HFpEF, consistent with impaired
lusitropic reserve [42].
In addition to diastolic reserve dysfunction, there are
commonly abnormalities in systolic responses to exercise
in HFpEF. Brubaker et al. and Borlaug et al. first showed
that chronotropic reserve is depressed in HFpEF, and
that this impairment is strongly associated with reduced
exercise capacity [15,41]. The cause for chronotropic incompetence is unknown and may be due to abnormalities in -adrenergic signaling [43] or to autonomic dysfunction, as these patients have also been shown to
display reduced heart rate recovery, abnormal baroreflex
sensitivity and enhanced cardiac sympathetic stimulation

[15,44]. Chronotropic incompetence in HFpEF has been

verified in several subsequent exercise studies [24,40,45],
challenging the conventional belief that heart rate slowing with pharmacotherapy is universally indicated in HFpEF. Therapies such as cardiac pacing are currently being
investigated in HFpEF and will be discussed subsequently.
Enhancement of contractility during exercise is also
impaired in HFpEF [15,19,23,24,40]. This may be related to subtle resting contractile dysfunction, abnormal calcium handling, passive stiffening, ischemia, oxidative stress, or abnormal myocardial energeticseach
of which may serve as a potential treatment target
[22,24,46,47]. In addition, normal exercise-induced reduction in vascular resistance is attenuated in HFpEF,
impairing cardiac output reserve, contributing to hypertensive responses to exercise and leading to abnormal
dynamic ventriculararterial coupling [15,19,39,40]. Abnormal vasodilation may be related to endothelial dysfunction, which is well-described in HFrEF [48]. Though
an initial study did not demonstrate abnormal flowmediated vasodilation in HFpEF [49], a more recent study
did show endothelial dysfunction in this group, and intriguingly, the extent of dysfunction was associated with
both lower exercise capacity and greater symptoms of
dyspnea and fatigue, suggesting that therapies targeting endothelial dysfunction may prove useful in HFpEF
[50].
VentricularArterial Stiffening
Arterial hypertension is almost universal in elderly patients with HFpEF [10,26], and this is related to both
ventricular and vascular stiffening [39,51]. Increased diastolic stiffness contributes to elevated filling pressures
at rest and with exercise, leading to dyspnea [6,8,9]. Increased systolic stiffness is also present in HFpEF [11], despite impaired chamber and myocardial contractility [22].
Ventricular-arterial coupling, defined by the ratio of arterial to ventricular systolic stiffness (elastance), is similar in HFpEF, healthy controls, and asymptomatic hypertensives [22]. However, while the coupling ratio is
preserved in HFpEF, its individual components (ventricular and arterial stiffness) are similarly and markedly
elevated. This causes greater increases in blood pressure,
cardiac work, and oxygen demand to deliver a given
stroke volume, limiting exercise capacity, and causing
more dramatic fluctuations in systemic pressures with
changes in preload and afterload [11,39,52]. Because
of increased systolic ventricular stiffening (steep endsystolic pressurevolume relationship), the patient with
HFpEF develops much more dramatic shifts in blood pressure with vasodilation or vasoconstriction [11]. The clinical correlate of this observation is that HFpEF patients

may be more prone to hypotension with overly aggressive diuresis or vasodilation. Alternatively, such patients
are also likely to develop hypertensive crisis and/or acute
pulmonary edema with dietary or medication nonadherence. The effects of ventricular-vascular stiffening on
hemodynamics and clinical behavior in HFpEF have been
reviewed in detail elsewhere [39].
Other Mechanisms
Recent data has demonstrated primary abnormalities
in volume handling [16,18,53], left atrial function
[17,54,55], pulmonary hypertension [21,26,56], autonomic dysfunction [15,44,45] and ventricular dyssynchrony [57,58] in HFpEF. Data from the Cardiovascular
Health Study showed that patients with HFpEF on average display increased ventricular diastolic dimensions
[18]. Earlier studies from this group similarly showed
larger chamber volumes by 3D echo, combined with increases in extracellular fluid volumesuggesting that filling pressures may be elevated in HFpEF primarily to
overfilling of the ventricle, rather than to an abnormally stiffened ventricle [16]. Other studies have not corroborated these findings [10,17,38], and further work is
required to clarify this question. Left atrial function is impaired in HFpEF [17,54], but it remains unknown how
this could be exploited therapeutically or whether any
such treatment would translate to clinical benefit. Pulmonary hypertension is very common in HFpEF, being
present in 80% of patients, and its presence and severity predict increased mortality [21,56]. Intriguingly, elderly patients presenting the pulmonary hypertension by
echo are more frequently found to display elevated left
ventricular filling pressures at catheterization, suggesting that many of these patients in fact have HFpEF [59].
Pulmonary-specific vasodilators have failed to show benefit in HFrEF and can in some patients exacerbate pulmonary venous hypertension [60]. Recently completed
[61] and ongoing studies [62] are examining the role for
pulmonary vasodilators in HFpEF. As in HFrEF, there is
evidence that both systolic and diastolic dyssynchrony exist in HFpEF [57,58], but the extent to which these abnormalities contribute to pathophysiology in HFpEF is
unknown, and it is further unclear whether this sort of
heterogeneous dyssynchrony could even be resynchronized [63].
A number of noncardiovascular mechanisms also contribute to the pathophysiology in chronic HF. Deconditioning is common, as patients withdraw from previously
more-active active lifestyles, and pulmonary abnormalities are frequently observed [64]. Qualitative and quantitative abnormalities in skeletal muscle function are welldescribed in HFrEF, contributing to symptoms of exercise
e9
intolerance and dyspnea, while also exacerbating sympathetic hyper-activation through ergoreflex stimulation
[6466]. While the latter mechanisms have not yet been
described in HFpEF, it is highly likely that they also play
important roles in contributing to symptoms of exertional
dyspnea and fatigue. Anemia and renal disease are welldescribed comorbidities in HF regardless of EF, and while
each is associated with increased mortality, it remains unclear whether or how treating these comorbidities might
improve outcome [6771].
HFpEF or Noncardiac Dyspnea?

Symptoms of exercise intolerance and exertional dyspnea
are highly sensitive for HF [72], but they are also very
nonspecific and may be attributable to a variety of noncardiac problems [7376]. As such, a number of investigators have appropriately emphasized that HFpEF may
be over-diagnosed in practice and in patients enrolled in
trials [7375]. Caruana et al. reported that the vast majority of patients in their series of HFpEF had at least one
alternative explanation for symptoms, such as obesity or
lung disease [73]. However, multiple causes for dyspnea (e.g., obesity, COPD, HFpEF) may coexist within the
same patient [77], and the presence of one source does
not exclude another. Biomarkers such as brain natriuretic
peptide (BNP and NT-proBNP) have emerged as valuable
noninvasive surrogates of elevated filling pressures and
diastolic dysfunction in HFpEF [78]. Ingle et al. recently

reported that while patients with HFpEF have similar objective and subjective exercise limitation as those with
HFrEF, their BNP levels were no different than normal
controls, suggesting that exertional symptoms may not be
due to heart failure [76]. Elevated natriuretic peptide levels predict increased risk for heart failure morbidity and
mortality [75], but they are also known to be lower on
average in HFpEF than HFrEF [79], and the absence of
BNP elevation does not necessarily exclude the diagnosis
of invasively confirmed HFpEF [80]. Even after a considerable battery of invasive and noninvasive evaluations,
the diagnosis of HFpEF may still remain unclear in many
cases, and until more gold standard diagnostic tests and
algorithms are validated, this uncertainty must be born
in mind when evaluating patients with normal EF and
dyspnea and considering the various treatment strategies
described further.
Conventional HF Therapies:
What Is the Evidence?
In contrast to HFrEF, outcome data from randomized trials in HFpEF had been lacking for some time,
though recent large trials have shed important new light
(Table 2). There are many reasons for the relative paucity
of data in HFpEFincluding limited appreciation of the
scope of the HFpEF epidemic, problems with accuracy
Table 2 Randomized controlled trials in heart failure with preserved ejection fraction
Trial
Drug
Inclusion criteria
Follow-up
Results
ACE-I/ARB
PEP-CHF [4]
Perindopril
70 years, HF, EF 40%
850
2.1 years
1 endpoint (death or HF hospitalization)

Death
HF hospitalization
Symptoms
Exercise capacity
CHARM-Preserved [3]
Candesartan
HF & EF > 40%
3023
37 months
1 Endpoint (CV death or HF hospitalization)

Death
HF hospitalization
I-PRESERVE [5]
Irbesartan
HF and EF > 45%
4128
4 years
1 endpoint (death or CV hospitalization)

Death
HF hospitalization
Beta blockers
Aronow et al. [91]
Propranolol
Post-MI, HF, EF 40%
158
12 months
death
EF
LV mass
Digoxin
Ancillary DIG [108]
Digoxin
HF and EF > 45%
988
37 months
1 endpoint (HF death or HF hospitalization)

Death
Hospitalization
e10

of diagnosis, difficulties enrolling HFpEF patients, who

are frequently older and have many comorbidities causing exclusion from trials, and the recent observation of
the importance of noncardiac complications in HFpEF patients, which importantly drive re-hospitalization rates
and overall mortality [81,82].
Angiotensin Converting Inhibitors

and Angiotensin Receptor Blockers
Medications that regulate the renin angiotensin system
are the best studied in hypertensive diastolic dysfunction
and HFpEF. Klingbeil et al. found in a meta-analysis of
hypertensive trials that LV mass was reduced most effectively by Angiotensin Receptor Blockers (ARBs) and
calcium channel blockers and least by -blockers and diuretics [83]. Little et al. showed in a study of 40 patients
with diastolic dysfunction and exercise-induced hypertension that losartan blunted this hypertensive response
and resulted in improved exercise tolerance compared to
hydrochlorothiazide [84]. The Valsartan in Diastolic Dysfunction (VALIDD) trial randomly assigned 384 patients
with hypertension and diastolic dysfunction (but no HF)
to aggressive antihypertensive therapy with valsartan or
placebo-based therapy [34]. While there was no benefit
to valsartan compared to other antihypertensives, blood
pressure reduction per se was associated with an improvement in diastolic LV relaxation, as estimated by tissue
Doppler echocardiography. However, none of these studies were performed in patients with a clinical diagnosis of
HFpEF.
Aronow and Kronzon first showed in a small, open
label study of patients with HFpEF and prior MI that
enalapril improved functional class and exercise time
while reducing LV mass [85]. The first large scale randomized study in HFpEF was the Candesartan in Heart
Failure-Assessment of Reduction in Mortality (CHARM)Preserved trial, comparing the ARB candesartan with
placebo [3]. After a median follow-up 36 months, treatment with candesartan was associated with a nonsignificant reduction in the composite endpoint in mortality
and cardiovascular hospitalizations, but the primary endpoint was not met [3]. More recently, the I-PRESERVE
(Irbesartan in Heart Failure with Preserved Systolic Function) trial assigned 4128 patients with HF and an EF
greater than 45% to irbesartan or placebo [5]. After
4 years of follow-up there was again no difference in
death or cardiovascular hospitalizations. These trials emphasize the disconnect in HFpEF literature between intermediate endpoints such as hypertrophy regression or
exercise capacity (both improved with ARBs [83,84]) and
clinical events.

The Perindopril in Elderly People with Chronic Heart

Failure (PEP-CHF) trial enrolled 850 patients aged
70 years to perindopril or placebo and found that
perindopril was associated with a trend toward decreased
all-cause mortality and hospitalization for heart failure at
1 year, but over the entire 3 year study period there was
no reduction in the primary endpoint [4]. However, there
was substantial cross over between treatment groups during the study, and event rates were lower than anticipated. In contrast to CHARM and I-PRESERVE, significant improvements in symptoms (New York Heart Association (NYHA) class) and functional status (6 min walk)
were seen in the perindopril arm, though secondary analyses must be viewed with caution in light of the negative
primary endpoint [3,5].
Beta Blockers
By slowing heart rate, -adrenergic antagonists may allow for a longer diastolic filling period. While this is
clearly useful with tachycardia or in patients with mitral stenosis, the utility of beta blockers in patients with
normal resting heart rates is unclear, because slowing
the heart rate in this range tends to simply prolong diastasis, where transmitral flow is absent [86]. Because
chronotropic incompetence is common in HFpEF and is
intimately linked to reduced exercise capacity [15,41],
beta-blockade may in fact worsen symptoms of exertional
intolerance. Unfortunately prospective trial data regarding beta blockers in HFpEF is lacking.
The Swedish Doppler-echocardiographic (SWEDIC)
trial randomized 113 patients with HFpEF (EF > 45%)
to carvedilol or placebo. After 6 months there was no improvement in a composite echo-Doppler diastolic function score [87]. A prospective observational study by
Dobre et al. showed that in HF patients with EF > 40%,
survival was increased in those prescribed -blockers
[88], but another recent observational study from Farasat
et al. found that beta blocker use may be associated
with increased risk for cardiovascular hospitalization in
women with HFpEF [89]. Retrospective analysis from the
large Organized Program to initiate Lifesaving Treatment
in Hospitalized Patients with Heart Failure (OPTIMIZEHF) registry showed that beta blocker use in HFpEF was
not associated with improved survival or a reduction in
hospitalizations, in striking contrast to observed findings
in HFrEFagain raising questions regarding the utility of
beta blockers in HFpEF [90].
An early open-label randomized trial in patients with
previous myocardial infarction, heart failure and an EF >
40% showed that propranolol compared to no propranolol improved mortality and increased ejection fraction after 1 year [91]. However, this population with
e11
prior Q-wave infarction and somewhat depressed LVEF

might have been expected to benefit more from betablockade than HFpEF patients without coronary disease
or as much systolic dysfunction (i.e., EF 4049%). The
more recent Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with
Heart Failure (SENIORS) Trial, which enrolled patients
aged 70 years with both reduced and preserved EF,
demonstrated the benefit of nebivolol versus placebo in
the primary outcome of mortality and cardiovascular hospitalization [92]. One subsequent analysis from SENIORS
suggested the benefits were restricted to those with reduced EF [93], whereas a more recent subanalysis indicated that the benefit was present regardless of EF [94].
Nebivolol is highly -1 specific and has additional nitric
oxide-dependent vasodilating properties, so these results
may not apply to other -blockers. Importantly, no trial
specifically enrolling nonischemic HFpEF with higher EF
(>50%) has been published to date, and there is concern
that many patients with mildly depressed EF (4049%)
may more closely resemble HFrEF than HFpEF. Prospective trial data on the effectiveness of beta-blockers in HFpEF patients that are representative of those seen in the
community are urgently needed.
Diuretics
As in HFrEF, diuretics play a key role in controlling symptoms of volume overload in HFpEF. By reducing central
congestion, the ventricle may operate in a more compliant portion of its pressurevolume relationship [95]. Diuretics are less useful in patients without clinical evidence
of volume overload, and because of enhanced preloadsensitivity in HFpEF, their use may be hazardous in euvolemic patients [39]. There is little data regarding diuretic
use in HFpEF. In a retrospective analysis of the ALLHAT
Trial, the thiazide diuretic chlorthalidone decreased the
incidence of HFpEF in hypertensive patients compared to
lisinopril, amlodipine, and doxazosin [96]. In the Hong
Kong Diastolic Heart Failure Study, patients with HFpEF
were randomized to diuretics alone or diuretics plus irbesartan or ramipril [97]. Quality of life scores improved in
all groups, leading the authors to conclude that diuretics improve symptoms in HFpEF, but absent a placebo
control, it cannot be determined how much of the symptomatic improvement was ascribable to diuretic therapy.
Nitrates
Direct nitric oxide (NO) donors such as nitrates increase cellular levels of cyclic guanosine monophosphate
(cGMP), a key second messenger that activates kinases
that may improve diastolic relaxation and compliance
e12
[98]. Nitrates also decrease preload, allowing the ventricle to function at lower volumes, where operating stiffness may be lower [25,99]. Despite a multitude of theoretical mechanisms of benefit to enhancing NO signaling in HFpEF, there is little clinical data. McCallister et al.
showed that administration of nitroglycerin can mitigate
the acute increase in LV filling pressures during supine
exercise in patients with coronary disease and normal
controls [100]. Use of short or long acting nitrates may
prove useful to treat symptoms of dyspnea in patients
with HFpEF, particularly when patients are euvolemic
and diuretics are not indicated. Novel therapies that enhance cGMP signaling appear promising and represent an
area of active investigation [101].
Calcium Channel Blockers

Setaro et al. showed in a study of 20 patients with HFpEF that treatment with verapamil compared to placebo
resulted in significantly reduced symptoms, increased
LV diastolic filling rates and increased mean exercise
time [102]. This was corroborated by Hung et al. in
similar echo-Doppler study [103]. Verapamil may also
reduce ventricular-arterial stiffening and improve exercise capacity in healthy older-aged patients [104]. By
regressing hypertrophy and controlling blood pressure,
dihydropyridine calcium channel blockers may prevent
or deter the development of HFpEF [83,96]. However,
as with -blockers, diuretics and nitrates, large scale
randomized trial data using calcium antagonists are not
available.
Aldosterone Antagonists
Aldosterone promotes cardiac hypertrophy and fibrosis [105], and its inhibition might be expected to reduce the ventricular-vascular stiffening and diastolic dysfunction characteristic of HFpEF. In a small randomized
study, Mottram et al. showed an improvement in several echocardiographic measures of myocardial function
in patients with hypertensive heart disease, normal EF
and exertional dyspnea with spironolactone [106]. The
large, NIH-sponsored TOPCAT trial comparing spironolactone to placebo in HFpEF is currently enrolling patients
and should help resolve this question.
Digitalis
While digoxin is often considered for its inotropic
actions in HFrEF, it also displays favorable effects
on baroreceptor function and reductions in sympathetic activation and neurohormonal stimulation, suggesting a potential role in HFpEF [107]. In an ancillary analysis of 988 patients with HFpEF (EF > 45%)

enrolled in the Digitalis Investigations Group (DIG) trial,

Ahmed et al. found that digoxin had no effect on heart
failure mortality or hospitalization [108]. At the protocolspecified 2 year follow up there was a reduction in HF
death or hospitalization (driven by the latter), but over
the median 37 month follow up, this difference was not
present. Of note, the majority of HFpEF patients in the
DIG trial had HF related to an ischemic etiology (56%),
and there was an unanticipated increase in hospitalizations for unstable angina in the digoxin group which
largely offset the nonsignificant reduction in HF hospitalization [108]. Ischemic disease is not the predominant
cause of HFpEF in population-based studies [1,2,26], and
as such, these results may not be applicable to many HFpEF patients encountered in the community.
Statins
In a prospective observational study of 137 HFpEF patients treated at the discretion of their primary physicians, Fukuta et al. found that after a mean follow-up
of 21 months, statin therapy was associated with significantly lower mortality (relative risk 0.20), whereas Angiotensin Converting Inhibitors (ACEI), ARB, -blockers,
and calcium channel blocker therapy had no association
with survival [109]. However, the GISSI-HF (Effect of rosuvastatin in patients with chronic heart failure) Trial,
which tested the effects of rosuvastatin on death and
death or cardiovascular hospitalization in patients with
chronic HF, found no benefit in the subgroup of patients
included with preserved EF (>40%; n = 465) [110].
Nonmedical Treatments
Revascularization
Myocardial ischemia acutely causes both systolic and
diastolic dysfunction [111], and may contribute to abnormal cardiovascular reserve with stress [15,112], suggesting that revascularization may be beneficial in patients with HFpEF. However, retrospective data suggests
that episodes of acute pulmonary edema tend to reoccur despite coronary revascularization in this population
[113], and while prospective data is lacking in HFpEF, the
recently presented heart failure revasculartization trial
(HEART) Trial observed no benefit to revascularization in
patients with HFrEF (EF 35%) and viable myocardium
[114]. HEART was underpowered due to low enrollment
(n = 69 randomized, n = 45 revascularized), and the unreported STITCH trial [115] may shed more light on the
role of revascularization in HF. Similar to HEART, this
trial included only patients with LV systolic dysfunction
(EF 35%). Until prospective data is available in HFpEF,

the role of coronary revascularization will remain unclear

and must be considered on a case-by-case basis.
Renal artery stenosis may cause paroxysmal hypertension and pulmonary edema, producing a form of secondary HFpEF. Renal revascularization percutaneously
or surgically in such patients can be extremely effective, and evaluation for renal artery stenosis is warranted
in patients with recalcitrant hypertension and episodes
of acute pulmonary edema, particularly if there is evidence of atherosclerosis elsewhere [116]. Enthusiasm has
been tempered with the recent publication of the Angioplasty and STent for Renal Artery Lesions (ASTRAL) Trial,
which found no benefit to renal revascularization regarding renal function or blood pressure control in patients
with renal artery stenosis [117]. However, this was not a
study of HF patients, who would be expected to be more
vulnerable to the effects of uncontrolled hypertension.
Indeed, it is established that renal revascularization effectively treats recurrent pulmonary edema in appropriately
selected HF patients with renal artery stenosis [118].
Exercise
Exercise capacity is reduced in HFpEF to a similar magnitude as seen in HFrEF [119]. Exercise programs improve
aerobic capacity and functional status in HFrEF [120] and
may potentially improve other abnormalities in HFpEF
such as endothelial dysfunction [50]. There is little published data regarding the role of exercise training in HFpEF, though two trials are currently examining this important question [121,122]. Cross-sectional data suggests
that conditioned athletes have better diastolic ventricular
compliance than apparently healthy sedentary patients
[123,124] and animal data from Brenner et al. suggest direct benefit of exercise training in the aging heart [125].
In contrast to possible beneficial effects on ventricular
compliance, Prasad et al. found in a cross sectional study
that prior endurance training among older subjects was
not associated with abrogation of age-associated deterioration in diastolic relaxation [126]. Longitudinal data are
lacking, and short-term interventional trials have demonstrated variable effects of exercise training upon diastolic
function [127].
Others
Diastolic stiffening of the ventricle in HFpEF increases reliance on the atrial contribution to filling. Accordingly,
loss of the latter with atrial fibrillation, which is common in HFpEF [26], can lead to clinical decompensation.
While trials of rate versus rhythm control have not been
performed in HFpEF, it is recommended that restoration
and maintenance of sinus rhythm be strongly considered
e13
in patients with HFpEF and atrial fibrillation [95]. Sleep

disordered breathing is common in all patients with HF,
and because obesity is a common risk factor for HFpEF,
sleep apnea should be evaluated for and treated in appropriate patients. As in HFrEF, anemia is common in HFpEF
[69], and trials of erythropoietin analogues are currently
enrolling [128].
Emerging Therapies and Future

Directions
With the failure of conventional HFrEF therapies noted
in published trials, current investigations are focusing
on novel therapeutic targets in HFpEF. Because of their
pleiotropic actions on multiple underlying mechanisms,
there is enthusiasm that phosphodiesterase-5 inhibitors
(PDE5I) may be efficacious in HFpEF. PDE5I attenuate
adrenergic stimulation [129], reduce ventricular-vascular
stiffening [130] and LV remodeling [131], improve endothelial function [132], and reduce pulmonary vascular resistance [133]. There is also evidence that they
may enhance renal responsiveness to endogenous natriuretic peptides [134]. The PDE5I sildenafil is currently
being tested in the ongoing RELAX (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes
and Exercise Ability in People With Diastolic Heart Failure) Trial [62], which will evaluate the effects of PDE5I
on exercise capacity, functional status and ventricular
form and function. Because aldosterone similarly displays adverse pleiotropic effects promoting ventricular
hypertrophy, fibrosis, vascular stiffening and endothelial
dysfunction [135], there is also hope that aldosterone
antagonists will be of benefit in HFpEF. The large
TOPCAT (Aldosterone Antagonist Therapy for Adults
with Heart Failure and Preserved Systolic Function)
trial, which will determine the role of spironolactone in
HFpEF, and is actively enrolling [136]. Finally, another class of agents that modulates both ventricular
and vascular function, the Rho-kinase inhibitors, also
may represent a potential novel therapeutic approach in
HFpEF. Rho-kinase inhibitors such as fasudil and Y27632 have demonstrated the ability to blunt progression
of cardiomyocyte hypertrophy and cardiac remodeling in
animal models of heart failure [137].
Modulation of heart rate is another area of active study.
Given the recent documentation of chronotropic incompetence in HFpEF [15,24,40,41], rate adaptive atrial pacing is currently being evaluated in the Restoration of
Chronotropic Competence in Heart Failure Patients With
Normal Ejection Fraction (RESET) trial, which will examine the effects of pacing on exercise capacity in patients with HFpEF [138]. In contrast, another trial is test-
e14
ing whether heart rate reduction using the If channel

blocker ivabradine may be of benefit [139]. Because autonomic dysfunction appears to play a role in HFpEF [15],
it has been postulated that direct carotid sinus stimulation
might improve symptoms in patients with HF via reduction in heart rate, improvements in baroreflex sensitivity, changes in nitric oxide bioavailability, antiarrhythmic
effects, or central modulation [140]. Currently there is
no data regarding effects of parasympathetic activation in
HFpEF.
Changes in myocyte stiffness and extracellular matrix are strongly implicated in the pathogenesis of abnormal chamber compliance in HFpEF [141]. This may
be due to both quantitative and qualitative changes in
collagen. Glucose crosslinking (glycation) increases with
aging and decreases tissue compliance, suggesting that
this may be a therapeutic target. Alagebrium chloride
(ALT-711) is a novel compound that breaks glucose
crosslinks and improves ventricular and arterial compliance in animals [142] and reduces blood pressure and
vascular stiffness in human hypertension [143]. ALT-711
was studied in an open label fashion in 23 patients with
HFpEF and shown to lead to reduction in left ventricular
mass and improvements in diastolic filling and quality of
life [144]. A placebo controlled, randomized trial of ALT711 was implemented but has since been terminated.
Transforming growth factor-beta (TGF-) is emerging as
an important pro-fibrotic hormone in cardiovascular diseases, and infusion of TGF- neutralizing antibody in a
rat model of pressure overload was associated with reduction in fibrosis and prevention of diastolic dysfunction
[145]. Matrix metalloproteinases play a role in modulating ventricular stiffening with hypertensive heart disease,
and therapies targeting these pathways may prove effective for HFpEF [146]. The cellular macromolecule titin
has emerged as a major determinant of resting myocyte
tension [147]. Titin is expressed as two isoforms in humans, the stiffer N2B and the more compliant N2BA, and
alteration of these expression patterns could be exploited
therapeutically. Recent studies have further shown that
titin has phosphorylation sites that dynamically regulate
its resting tension, and these represent exciting new targets for drug development [147149].
Because both systolic and diastolic ventricular reserve
responses with exercise are impaired in HFpEF, it seems
plausible that there might be a problem with myocyte energy utilization or availability [6,15,24]. Smith et al. first
showed abnormal ATP phosphocreatine shuttle kinetics
in HFpEF [46], and these results has more recently been
confirmed by Phan et al. [24]. As such, novel therapies
targeting myocardial energy substrate utilization may be
useful in HFpEF and are currently under investigation
[150].

Oxidative stress in common in HFrEF and promotes

ventricular and endothelial dysfunction. Xanthine oxidase inhibitors such as allopurinol have been shown to
reduce oxidative stress and improve myocardial contractile reserve acutely in HFrEF [151], though a subsequent
clinical trial did not show a benefit [152]. Oxidative stress
promotes uncoupling of nitric oxide synthase (NOS), and
the consequent loss of downstream effectors (cGMP) may
exacerbate diastolic dysfunction, promote maladaptive
remodeling, and produce endothelial dysfunction. Treatment with tetrahydrobiopterin (BH4 ), an essential cofactor of endothelial NOS, has recently been shown in animal models of pressure overload to attenuate remodeling
and improve NOS coupling [153]. Treatments designed
to re-couple NOS and/or improve cGMP signaling may
eventually prove useful in HFpEF [101,154].
The anti-anginal drug ranolazine has been postulated as a potential treatment for HFpEF, as it blocks
inward sodium current and thereby reduces myocyte
calcium levels, possibly enhancing relaxation and/or
diastolic stiffness, as suggested in animal studies [155].
However, this treatment remains to be tested in human
HFpEF. Finally, mechanical devices designed to improve
early diastolic relaxation and enhance ventricular suction are currently being developed and studied in animal models, though data is very preliminary. These devices work by storing energy expended during systolic
contraction to enhance recoil and suction during early
diastole.
Conclusions
HFpEF remains a major public health problem, but unfortunately there is little evidence guiding how best to
treat it. In the absence of trial data documenting benefit, current guidelines simply emphasize control of blood
pressure and volume overload [27]. Importantly, careful
follow up is paramount in HFpEF, particularly among the
elderly, because commonly used medications such as vasodilators and diuretics may produce exaggerated drops
in blood pressure because of ventricular-arterial stiffening, while beta blockers or nondihydropyridine calcium
antagonists may exacerbate pre-existing chronotropic incompetence. Recent work has emphasized the importance of noncardiac comorbidities in HFpEF, and in the
absence of therapies of proven efficacy, it is essential to
treat these accordingly. Important steps have been made
in our mechanistic understanding of HFpEF over the past
10 years, and these and further advances will hopefully
allow for the design of better and more specific treatments for this ever-expanding half of the heart failure
population.

Conict of Interest
There are no conflicts of interest or financial disclosures.
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Heart Failure with Preserved Ejection Fraction:

c 2010 Blackwell Publishing Ltd

Heart Failure with Preserved Ejection Fraction

A.M. From and B.A. Borlaug

Table 1 Pathophysiologic mechanisms of heart failure with preserved ejection fraction

1. LV relaxation rate and

Dyspnea at rest or exertion

Kitzman [6], Gandhi [7], Zile [8],

1. Minimal effects at rest

Minimal sequelae at rest

Liu [47], Yip [12], Yu [13], Petrie [14],

1. Changes in blood pressure

Hypotension and oliguria with

Chen [51], Kawaguchi [11], Borlaug

Vascular stiffening and

Hypertensive response to exercise

Kawaguchi [11], Hundley [52], Borlaug

1. Extracellular uid volume

Dyspnea at rest or exertion

Maurer [16, 18], Kitzman [119],

Left atrial dysfunction

1. Atrial contractility and atrial

Dyspnea at rest or exertion

Melenovsky [17], Gottdiener [54]

1. Right ventricular afterload

Dyspnea at rest or exertion

Klapholz [26], Lam [21], Kjaergaard [56]

Borlaug [15], Brubaker [41]

1. Cardiac output to maintain

Felker [69], Latado [71]

Described in HFrEF and presumed to contribute to HFpEF but not described.

c 2010 Blackwell Publishing Ltd

Heart Failure with Preserved Ejection Fraction

[28] believed that diastolic dysfunction lies at the center

A.M. From and B.A. Borlaug

Using load-independent measures, Baicu et al. found no

Cardiovascular Reserve Function in HFpEF

c 2010 Blackwell Publishing Ltd

A.M. From and B.A. Borlaug

[15,44]. Chronotropic incompetence in HFpEF has been

c 2010 Blackwell Publishing Ltd

Heart Failure with Preserved Ejection Fraction

Heart Failure with Preserved Ejection Fraction

HFpEF or Noncardiac Dyspnea?

A.M. From and B.A. Borlaug

diastolic dysfunction in HFpEF [78]. Ingle et al. recently

70 years, HF, EF 40%

1 endpoint (death or HF hospitalization)

HF & EF > 40%

1 Endpoint (CV death or HF hospitalization)

HF and EF > 45%

1 endpoint (death or CV hospitalization)

Post-MI, HF, EF 40%

HF and EF > 45%

1 endpoint (HF death or HF hospitalization)

c 2010 Blackwell Publishing Ltd

Heart Failure with Preserved Ejection Fraction

A.M. From and B.A. Borlaug

of diagnosis, difficulties enrolling HFpEF patients, who

Angiotensin Converting Inhibitors

c 2010 Blackwell Publishing Ltd

The Perindopril in Elderly People with Chronic Heart

Heart Failure with Preserved Ejection Fraction